Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico
Cells constantly adapt and respond to molecular changes in their microenvironment. The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is sensitive to endogenous (oxygen tension, redox potential) and exogenous (polyaromatic hydrocarbons -aryls- and environmental toxins) facto...
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| Autores principales: | , , |
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| Formato: | Artículo revista |
| Lenguaje: | Español |
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Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología
2023
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| Materias: | |
| Acceso en línea: | https://revistas.unc.edu.ar/index.php/med/article/view/42734 |
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I10-R327-article-42734 |
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ojs |
| institution |
Universidad Nacional de Córdoba |
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I-10 |
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R-327 |
| container_title_str |
Revista de la Facultad de Ciencias Médicas de Córdoba |
| language |
Español |
| format |
Artículo revista |
| topic |
naringin Estrogen Receptor ARYL RECEPTOR in sílico BINDING ASSAYS naringina RECEPTOR DE ESTRÓGENO RECEPTOR DE ARILOS in sílico ENSAYOS DE UNION . |
| spellingShingle |
naringin Estrogen Receptor ARYL RECEPTOR in sílico BINDING ASSAYS naringina RECEPTOR DE ESTRÓGENO RECEPTOR DE ARILOS in sílico ENSAYOS DE UNION . Cossy Isasi , S Rivoira , MA Muiño, JC Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico |
| topic_facet |
naringin Estrogen Receptor ARYL RECEPTOR in sílico BINDING ASSAYS naringina RECEPTOR DE ESTRÓGENO RECEPTOR DE ARILOS in sílico ENSAYOS DE UNION . |
| author |
Cossy Isasi , S Rivoira , MA Muiño, JC |
| author_facet |
Cossy Isasi , S Rivoira , MA Muiño, JC |
| author_sort |
Cossy Isasi , S |
| title |
Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico |
| title_short |
Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico |
| title_full |
Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico |
| title_fullStr |
Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico |
| title_full_unstemmed |
Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico |
| title_sort |
possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico |
| description |
Cells constantly adapt and respond to molecular changes in their microenvironment. The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is sensitive to endogenous (oxygen tension, redox potential) and exogenous (polyaromatic hydrocarbons -aryls- and environmental toxins) factors. Activated AHR translocates to the nucleus and remains inactive in the cytosol complexed with other proteins (HSP90, AIP or XAP2, p23 and SRC). The AHR complex and its translocator protein interact with the estrogen receptor (ESR). Estradiol represses AHR in granulosa and ovarian tissue. AHR causes degradation of ESR by proteasome. Activation of AHR by cigarette smoke targets pathogenic TH17 cells to autoimmunity and activates mast cells and macrophages in allergies. Naringin (NGN) is an antitumor flavonoid that inhibits aromatase activity. In silico studies place NGN in the ligand niche in ESR. But NGN is 1000 times more soluble than estradiol, which represents a thermodynamic barrier. We investigated the interaction of ESR and AHR with NGN in silico.
We employed 1GWR, 7ZUB structures (RSCB PDB), respectively that were edited to perform blind binding assays (without posing the ligand in the ligand domain) with implicit solvent and molecular dynamics in explicit solvent with widely used free software (OpenChimera, AutoDock, EADock, CharMM forcefields, NAMD). NGN conformations were obtained from ZINC and PubChem and minimized prior to testing.
We found that the minimum binding delta Gs are similar (ESR -8.32 ± 0.34 and AHR -7.56 ± 0.41 Kcal/mol+- sigma) with NGN outside the ligand niche. The Van der Waals volume of NGN would correspond to that of the interactions of ESR-Corepressor and AHR-AIP.
These observations are contrary to what is reported in the literature, but coincide with structures of NGN bound to MIF observed by RX diffraction (RSCB PDB). It remains to be determined whether NGN competes with ESR Corepressor and AIP for their respective binding sites and whether NGN-XR complexes have different affinity for natural ligands to construct any rigorous mechanistic hypothesis, which requires greater computational power. |
| publisher |
Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología |
| publishDate |
2023 |
| url |
https://revistas.unc.edu.ar/index.php/med/article/view/42734 |
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I10-R327-article-427342023-10-19T21:19:32Z Possible molecular interactions of naringin with the estrogen receptor and the aryl hydrocarbon receptor studied in silico Interacciones moleculares posibles de naringina con el receptor de estrógeno y el receptor de arilos estudiadas in silico . Cossy Isasi , S Rivoira , MA Muiño, JC naringin Estrogen Receptor ARYL RECEPTOR in sílico BINDING ASSAYS naringina RECEPTOR DE ESTRÓGENO RECEPTOR DE ARILOS in sílico ENSAYOS DE UNION . Cells constantly adapt and respond to molecular changes in their microenvironment. The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is sensitive to endogenous (oxygen tension, redox potential) and exogenous (polyaromatic hydrocarbons -aryls- and environmental toxins) factors. Activated AHR translocates to the nucleus and remains inactive in the cytosol complexed with other proteins (HSP90, AIP or XAP2, p23 and SRC). The AHR complex and its translocator protein interact with the estrogen receptor (ESR). Estradiol represses AHR in granulosa and ovarian tissue. AHR causes degradation of ESR by proteasome. Activation of AHR by cigarette smoke targets pathogenic TH17 cells to autoimmunity and activates mast cells and macrophages in allergies. Naringin (NGN) is an antitumor flavonoid that inhibits aromatase activity. In silico studies place NGN in the ligand niche in ESR. But NGN is 1000 times more soluble than estradiol, which represents a thermodynamic barrier. We investigated the interaction of ESR and AHR with NGN in silico. We employed 1GWR, 7ZUB structures (RSCB PDB), respectively that were edited to perform blind binding assays (without posing the ligand in the ligand domain) with implicit solvent and molecular dynamics in explicit solvent with widely used free software (OpenChimera, AutoDock, EADock, CharMM forcefields, NAMD). NGN conformations were obtained from ZINC and PubChem and minimized prior to testing. We found that the minimum binding delta Gs are similar (ESR -8.32 ± 0.34 and AHR -7.56 ± 0.41 Kcal/mol+- sigma) with NGN outside the ligand niche. The Van der Waals volume of NGN would correspond to that of the interactions of ESR-Corepressor and AHR-AIP. These observations are contrary to what is reported in the literature, but coincide with structures of NGN bound to MIF observed by RX diffraction (RSCB PDB). It remains to be determined whether NGN competes with ESR Corepressor and AIP for their respective binding sites and whether NGN-XR complexes have different affinity for natural ligands to construct any rigorous mechanistic hypothesis, which requires greater computational power. Las células se adaptan y responden constantemente a los cambios moleculares en su microentorno. El factor de transcripción activado por ligando, receptor de hidrocarburo arilo (AHR), es sensible a factores endógenos (tensión de oxígeno, potencial redox) y exógenos (hidrocarburos poliaromáticos -arilos- y toxinas ambientales). AHR activado transloca al núcleo y se mantiene inactivo en el citosol acomplejado con otras proteínas (HSP90, AIP o XAP2, p23 y SRC). El complejo AHR y su proteína translocadora interaccionan con el receptor de estrógeno (ESR). Estradiol reprime AHR en granulosa y en tejido ovárico. AHR provoca la degradación de ESR por proteasoma. La activación de AHR por humo de cigarrillo orienta células TH17 patógenas a la autoinmunidad y activa mastocitos y macrófagos en alergias. Naringina (NGN) es un flavonoide antitumoral que inhibe la actividad aromatasa. Estudios in silico sitúan a NGN en el nicho del ligando en ESR. Pero NGN es 1000 veces más soluble que estradiol, lo que supone una barrera termodinámica. Investigamos la interacción de ESR y AHR con NGN in silico. Empleamos estructuras 1GWR, 7ZUB (RSCB PDB), respectivamente que se editaron para hacer los ensayos de unión a ciego (sin obligar el ligando a una ubicación predefinida) con solvente implícito y dinámica molecular en solvente explícito con sofware gratuito de uso generalizado (OpenChimera, AutoDock, EADock, CharMM forcefields, NAMD). Las conformaciones de NGN fueron obtenidas de ZINC y PubChem y minimizadas previo a los ensayos. Encontramos que los deltaG de unión mínimos son similares (ESR -8,32 ± 0,34 y AHR -7,56 ± 0,41 Kcal/mol+- sigma) con NGN por fuera del nicho del ligando. El volumen de Van der Waals de NGN correspondería al de las interacciones ESR-Correpresor de ESR y AHR-AIP. Estas observaciones se contraponen a lo referido en bibliografía, pero coinciden con estructuras de NGN unida a MIF observadas por difracción de RX (RSCB PDB). Queda por determinar si NGN compite con Correpresor de ESR y con AIP por sus respectivos sitios de unión y si los complejos NGN-XR tienen diferente afinidad por los ligandos naturales para elaborar alguna hipótesis mecanística rigurosa, lo que requiere mayor potencia computacional. . Universidad Nacional Córdoba. Facultad de Ciencias Médicas. Secretaria de Ciencia y Tecnología 2023-10-19 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion application/pdf https://revistas.unc.edu.ar/index.php/med/article/view/42734 Revista de la Facultad de Ciencias Médicas de Córdoba.; Vol. 80 (2023): Suplemento JIC XXIV Revista de la Facultad de Ciencias Médicas de Córdoba; Vol. 80 (2023): Suplemento JIC XXIV Revista da Faculdade de Ciências Médicas de Córdoba; v. 80 (2023): Suplemento JIC XXIV 1853-0605 0014-6722 spa https://revistas.unc.edu.ar/index.php/med/article/view/42734/42790 Derechos de autor 2023 Universidad Nacional de Córdoba http://creativecommons.org/licenses/by-nc/4.0 |